Pharmaceutical compositions comprising meloxicam

ABSTRACT

Disclosed herein is a method of treating migraine in patients with a history of inadequate response to prior migraine treatments comprising: selecting a patient who, for at least the past month: 1) has had 2 to 8 migraines per month, and 2a) according to the patient, is never or rarely comfortable enough with the patient&#39;s migraine medication to be able to plan daily activities, 2b) according to the patient, after taking migraine medication, the patient never or rarely feels in control of the patient&#39;s migraines enough so that the patient feels there will be no disruption in the patient&#39;s daily activities, 2c) has an mTOQ-4 score of 0, and/or 2d) has a history of depression; and administering a combination of 20 mg of meloxicam and 10 mg of rizatriptan to the patient during a migraine attack.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Patent ApplicationNo. PCT/US2023/067172, filed May 18, 2023; which claims priority to U.S.Provisional Pat. App. No. 63/343,982, filed May 19, 2022; all of whichare expressly incorporated by reference herein in their entirety.

SUMMARY

Some embodiments include a method of treating migraine in patients witha history of inadequate response to prior migraine treatmentscomprising, selecting a patient who, for at least the past fourweeks: 1) has had 2 to 8 migraines per month, and 2) according to thepatient, is never or rarely comfortable enough with the patient'smigraine medication to be able to plan daily activities; and after thepatient is selected, administering a combination of 20 mg of meloxicamor a pharmaceutically acceptable salt thereof and 10 mg of rizatriptanor a pharmaceutically acceptable salt thereof to the patient during amigraine attack.

Some embodiments include a method of treating migraine in patients witha history of inadequate response to prior migraine treatmentscomprising, selecting a patient who, for at least the past fourweeks: 1) has had 2 to 8 migraines per month and, 2) according to thepatient, after taking the migraine medication, the patient never orrarely feels in control of the patient's migraines enough so that thepatient feels there will be no disruption in the patient's dailyactivities; and after the patient is selected, administering acombination of 20 mg of meloxicam or a pharmaceutically acceptable saltthereof and 10 mg of rizatriptan or a pharmaceutically acceptable saltthereof to the patient during a migraine attack.

Some embodiments include a method of treating migraine in patients witha history of inadequate response to prior migraine treatmentscomprising, selecting a patient who, for at least the past fourweeks: 1) has had 2 to 8 migraines per month and, 2) has an mTOQ-4 scoreof 0; and after the patient is selected, administering a combination of20 mg of meloxicam or a pharmaceutically acceptable salt thereof and 10mg of rizatriptan or a pharmaceutically acceptable salt thereof to thepatient during a migraine attack.

Some embodiments include a method of treating migraine in patients witha history of inadequate response to prior migraine treatmentscomprising, selecting a patient who: 1) has had 2 to 8 migraines permonth for at least the past four weeks, and 2) has a history ofdepression; and after the patient is selected, administering acombination of 20 mg of meloxicam or a pharmaceutically acceptable saltthereof and 10 mg of rizatriptan or a pharmaceutically acceptable saltthereof to the patient during a migraine attack.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows plots of the percentages of subjects reporting pain reliefat various time points over the first 4 hours post dose of the dosageforms of Meloxicam/Rizatriptan, rizatriptan, MoSEIC meloxicam, andplacebo described in Example 1.

FIG. 1A shows the percentage of subjects reporting pain relief overplacebo for meloxicam, rizatriptan, and meloxicam/rizatriptan at 1.0hour and 1.5 hours.

FIG. 2 shows the percentages of subjects achieving pain freedom at 2hours, 4 hours, 12 hours, and 16 hours post dose of the dosage forms ofMeloxicam/Rizatriptan, rizatriptan, MoSEIC meloxicam, and placebodescribed in Example 1.

FIG. 3A shows the percentages of subjects achieving sustained painfreedom from 2 hours to 24 hours post dose of the dosage forms ofMeloxicam/Rizatriptan, rizatriptan, MoSEIC meloxicam, and placebodescribed in Example 1.

FIG. 3B shows the percentages of subjects achieving sustained painrelief from 2 hours to 24 hours post dose of the dosage forms ofMeloxicam/Rizatriptan, rizatriptan, MoSEIC meloxicam, and placebodescribed in Example 1.

FIG. 4A shows the percentages of subjects achieving sustained painfreedom from 2 hours to 48 hours post dose of the dosage forms ofMeloxicam/Rizatriptan, rizatriptan, MoSEIC meloxicam, and placebodescribed in Example 1.

FIG. 4B shows the percentages of subjects achieving sustained painrelief from 2 hours to 48 hours post dose of the dosage forms ofMeloxicam/Rizatriptan, rizatriptan, MoSEIC meloxicam, and placebodescribed in Example 1.

FIG. 4C shows the percentage of subjects achieving sustained painfreedom over placebo from 2 hours to 48 hours for meloxicam,rizatriptan, and meloxicam/rizatriptan.

FIG. 4D shows the percentage of subjects achieving sustained pain reliefover placebo from 2 hours to 48 hours for meloxicam, rizatriptan, andmeloxicam/rizatriptan.

FIG. 5 shows the percentages of subjects who took rescue medicationthrough hour 24 post dose of the dosage forms of Meloxicam/Rizatriptan,rizatriptan, MoSEIC meloxicam, and placebo described in Example 1.

FIG. 6 depicts the proportion of patients in Example 1 answering “never”or “rarely” to each of the mTOQ-4 questions.

FIG. 7A and FIG. 7B show the percentage of subjects having freedom frompain and resolution of most bothersome symptom for subjects takingmeloxicam/rizatriptan and placebo in Example 3.

FIG. 8 shows the percentage of subjects achieving pain freedom over timefor subjects taking meloxicam/rizatriptan and placebo in Example 3.

FIG. 9 shows the percentage of subjects achieving freedom from mostbothersome symptom over time for subjects taking meloxicam/rizatriptanand placebo in Example 3.

FIG. 10A and FIG. 10B show the percentage of subjects achieving painfreedom over hours 2-24 and hours 2-48 for subjects takingmeloxicam/rizatriptan and placebo in Example 3.

FIG. 11 shows the percentage of subjects achieving freedom from painprogression over hours 2-24 for subjects taking meloxicam/rizatriptanand placebo in Example 3.

FIG. 12 shows the percentage of subjects taking rescue medication forsubjects taking meloxicam/rizatriptan and placebo in Example 3.

FIG. 13 shows the percentage of subjects having no functional disabilityat hour 24 for subjects taking meloxicam/rizatriptan and placebo inExample 3.

FIG. 14 shows the percentage of subjects having a Patient GlobalImpression of Change (PGI-C) of “very much improved” or “much improved”at hour 2 for subjects taking meloxicam/rizatriptan and placebo inExample 3.

FIG. 15 shows the 24-hour sustained pain freedom rates compared toplacebo for patients with higher BMI, allodynia, morning migraine, and ahistory of depression.

DETAILED DESCRIPTION

Meloxicam, which has the structure:

is a nonsteroidal anti-inflammatory (NSAID) drug that exhibitsanti-inflammatory, analgesic, and antipyretic activities. The meloxicammechanism of action may be related to prostaglandin synthetase(cyclo-oxygenase, COX) inhibition which is involved in the initial stepsof the arachidonic acid cascade, resulting in the reduced formation ofprostaglandins, thromboxanes and prostacyclin.

Meloxicam and some other NSAIDs have poor aqueous solubility which mayreduce bioavailability and slow the onset of pain relief resulting fromtheir use. One means of increasing the solubility and bioavailability ofmeloxicam is through the use of cyclodextrins. Cyclodextrin (also knownas cycloamyloses) are generally cyclic polysaccharides which form abucket-like shape. Cyclodextrins help to increase bioavailability ofother molecules because cyclodextrins are hydrophobic on the inside andhydrophilic on the outside which helps to facilitate the transport ofmolecules, such as hydrophobic molecules. The naturally occurringcyclodextrins include six, seven, and eight glucose units (α, β, andγ-cyclodextrin, respectively). However, synthetic cyclodextrinscontaining more or less glucose units are possible. In aqueoussolutions, cyclodextrins can form complexes (i.e., an inclusion complex)with drugs by incorporating the drug into the center/hydrophobic portionof the cyclodextrin ring; although cyclodextrin compounds are also knownto aggregate around a drug in a micelle-type structure. This ability ofcyclodextrins may allow them to act as carriers of drugs to increase thebioavailability of less soluble drugs.

A combination of rizatriptan and meloxicam (referred to herein forconvenience as a “subject combination”) may be used to treat a varietyof pain conditions.

Rizatriptan has the structure shown below.

Some embodiments include a subject combination comprising: 1) aninclusion complex of meloxicam and a cyclodextrin, 2) rizatriptan, and3) a bicarbonate for treating migraine in a human being. The migrainemay be treatment-resistant migraine. The human being may have a historyof inadequate response to prior treatments. In some embodiments, thecyclodextrin is SBEβCD.

A dosage form may be given enterally including, but not limited to,oral, sublingual, or rectal delivery, or parenterally including, but notlimited to, intravenous, intramuscular, intranasal, or subcutaneousdelivery.

Unless otherwise indicated, any reference to a compound herein, such asmeloxicam or rizatriptan, by structure, name, or any other means,includes pharmaceutically acceptable salts, alternate solid forms, suchas polymorphs, solvates, hydrates, enantiomers, tautomers,deuterium-modified forms, or any other chemical species, such asprecursors, prodrugs, or any other chemical species that may rapidlyconvert to a compound described herein under conditions in which thecompounds are used as described herein.

A subject combination may be given enterally including, but not limitedto, oral, sublingual, or rectal delivery, or parenterally including, butnot limited to, intravenous, intramuscular, intranasal, or subcutaneousdelivery. In some embodiments, both meloxicam and rizatriptan areadministered orally.

Normally, the combination of meloxicam and rizatriptan is administeredso that the human being receives the meloxicam and rizatriptan within ashort period of time with respect to one another. For example, themeloxicam and rizatriptan may be administered within about 2 hours,within about 1 hour, within about 30 minutes, within about 20 minutes,within about 15 minutes, within about 10 minutes, within about 5minutes, or within about 1 minute of one another. In some embodiments,the meloxicam and rizatriptan are administered simultaneously, which forthe purpose of this disclosure includes administration within about 5minutes. In some embodiments, the meloxicam and rizatriptan areadministered in a single dosage form, such as a solid dosage form (e.g.,an oral solid dosage form for direct oral administration).

The term “treating”, or “treatment” broadly includes any kind oftreatment activity, including the diagnosis, cure, mitigation, orprevention of disease in man or other animals, or any activity thatotherwise affects the structure or any function of the body of man orother animals.

Migraine is a disabling neurological disorder characterized by recurrentattacks of pulsating head pain accompanied by nausea and sensitivity tolight and sound. This pain may be mild, or moderate to severe, but isoften severe and incapacitating, requiring bed rest. The headaches mayaffect one half of the head, may be pulsating in nature, and may lastfrom 2 to 72 hours. Associated symptoms may include nausea, vomiting,and sensitivity to light (photophobia), sound (phonophobia), or smell.The migraine pain may be accompanied by disturbed vision. The migrainepain can be made worse by physical activity. Migraines may be associatedwith an aura, which may be a short period of visual disturbance whichsignals that the headache will soon occur. Some migraine patients maynot have aura.

In some embodiments, the human being who is being treated for migrainepain suffers from allodynia, such as cutaneous allodynia with theirmigraine attacks. Allodynia, such as cutaneous allodynia, which is painfrom normally non-painful stimuli (such as brushing hair, wearingglasses, taking a shower, etc.). Patients having allodynia, such ascutaneous allodynia are believed to be less likely to respond well totriptan medications.

Current treatments are suboptimal, with more than 70% of sufferersreporting dissatisfaction with existing acute treatments. The mostcommonly reported reasons for patient dissatisfaction are slow onset ofpain relief, inconsistent pain relief, and recurrence of pain during thesame day. Suboptimal acute treatment is associated with a significantlyincreased risk of new-onset chronic migraine, which may be prevented byimproving acute treatment outcomes.

Administering a subject combination to a human being suffering frommigraine, such as an acute attack of migraine pain or aura, may quicklyresult in a reduction in a migraine symptom, such as pain, nausea,vomiting, photophobia, or phonophobia, such as at or within about 5minutes (intended as a shorthand for “at about 5 minutes, or withinabout 5 minutes”), at or within about 10 minutes, at or within about 30minutes, at or within about 1 hour, at or within about 90 minutes, at orwithin about 2 hours, at or within about 2.5 hours, or at or withinabout 3 hours. In some embodiments, a human being experiences areduction of, or complete relief from, pain, such as headache pain ormigraine pain, nausea, vomiting, photophobia, and/or phonophobia, at orwithin about 1 hour, at or within about 90 minutes, at or within about 2hours, at or within about 2.5 hours, or at or within about 3 hours. Insome embodiments, the relief experienced, is greater than would beexperienced by receiving the same amount of rizatriptan withoutmeloxicam. In some embodiments, the relief experienced, is greater thanwould be experienced by receiving the same amount of meloxicam withoutrizatriptan.

The subject combination may be administered at the earliest sign ofmigraine pain, or soon after the earliest sign of migraine, such aswithin about 1 minute, within about 5 minutes, within about 10 minutes,within about 15 minutes, within about 20 minutes, within about 30minutes, or within about 1 hour. At this early state, the pain may stillbe mild, or before the pain progresses to moderate or severe intensity.For some methods, the subject combination may be administered when themigraine pain has reached moderate or severe intensity.

In some embodiments, the combination of meloxicam and rizatriptan isadministered to a human migraine patient having, or who is selected forhaving, functional disability. In some embodiments, the treatmentresults in the human migraine patient being able to return to normalactivities within 24 hours after receiving the treatment.

The combination of meloxicam and rizatriptan may have distinct dualmechanisms of action for the acute treatment of migraine. Meloxicam is apotent, COX-2 preferential NSAID which is limited by slow absorption.Rizatriptan is a potent 5-HT1_(B/D) agonist believed to have efficacy inmigraine.

Observation of relief or reduction in a symptom at a specific period oftime, such as “at 2 hours,” is useful because it allows theeffectiveness of the treatment to be evaluated at a specific orconsistent time point, which facilitates comparison between patients.Observation of relief or reduction in a symptom within a specific periodof time, such as “within about 2 hours,” is useful because it isdesirable for relief or reduction of a symptom to occur as early aspossible, and specifying that relief occur within a specified time setsa guideline in which it is desirable that relief occur.

For some methods, administration of the subject combination may achievea reduction in migraine pain, nausea, vomiting, photophobia, orphonophobia that lasts at least about one hour, at least about twohours, at least about three hours, at least about four hours, at leastabout six hours, at least about eight hours, about 8-24 hours, about 24hours, or more than 24 hours.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form for direct oraladministration), and two hours after the meloxicam and the rizatriptanare administered, the human being experiences greater pain relief thanthe human being would have experienced two hours after receiving thesame amount of meloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid dosage form), and twenty-fourhours after the meloxicam and the rizatriptan are administered, thehuman being experiences greater pain relief than the human being wouldhave experienced twenty-four hours after receiving the same amount ofmeloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and two hoursafter the meloxicam and the rizatriptan are administered, the humanbeing experiences greater pain relief than the human being would haveexperienced two hours after receiving the same amount of rizatriptanwithout the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and twenty-fourhours after the meloxicam and the rizatriptan are administered, thehuman being experiences greater pain relief than the human being wouldhave experienced twenty-four hours after receiving the same amount ofrizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and two hoursafter the meloxicam and the rizatriptan are administered, the humanbeing experiences greater relief from nausea than the human being wouldhave experienced two hours after receiving the same amount of meloxicamwithout the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and twenty-fourhours after the meloxicam and the rizatriptan are administered, thehuman being experiences greater relief from nausea than the human beingwould have experienced twenty-four hours after receiving the same amountof meloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and two hoursafter the meloxicam and the rizatriptan are administered, the humanbeing experiences greater relief from nausea than the human being wouldhave experienced two hours after receiving the same amount ofrizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and twenty-fourhours after the meloxicam and the rizatriptan are administered, thehuman being experiences greater relief from nausea than the human beingwould have experienced twenty-four hours after receiving the same amountof rizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and two hoursafter the meloxicam and the rizatriptan are administered, the humanbeing experiences greater relief from vomiting than the human beingwould have experienced two hours after receiving the same amount ofmeloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and twenty-fourhours after the meloxicam and the rizatriptan are administered, thehuman being experiences greater relief from vomiting than the humanbeing would have experienced twenty-four hours after receiving the sameamount of meloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and two hoursafter the meloxicam and the rizatriptan are administered, the humanbeing experiences greater relief from vomiting than the human beingwould have experienced two hours after receiving the same amount ofrizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and twenty-fourhours after the meloxicam and the rizatriptan are administered, thehuman being experiences greater relief from vomiting than the humanbeing would have experienced twenty-four hours after receiving the sameamount of rizatriptan without the meloxicam. In some embodiments, themeloxicam and the rizatriptan are administered simultaneously (e.g., ina single dosage form, such as a single oral dosage form, including asingle solid oral dosage form), and two hours after the meloxicam andthe rizatriptan are administered, the human being experiences greaterrelief from photophobia than the human being would have experienced twohours after receiving the same amount of meloxicam without therizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and twenty-fourhours after the meloxicam and the rizatriptan are administered, thehuman being experiences greater relief from photophobia than the humanbeing would have experienced twenty-four hours after receiving the sameamount of meloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and two hoursafter the meloxicam and the rizatriptan are administered, the humanbeing experiences greater relief from photophobia than the human beingwould have experienced two hours after receiving the same amount ofrizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and twenty-fourhours after the meloxicam and the rizatriptan are administered, thehuman being experiences greater relief from photophobia than the humanbeing would have experienced twenty-four hours after receiving the sameamount of rizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and two hoursafter the meloxicam and the rizatriptan are administered, the humanbeing experiences greater relief from phonophobia than the human beingwould have experienced two hours after receiving the same amount ofmeloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and twenty-fourhours after the meloxicam and the rizatriptan are administered, thehuman being experiences greater relief from phonophobia than the humanbeing would have experienced twenty-four hours after receiving the sameamount of meloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and two hoursafter the meloxicam and the rizatriptan are administered, the humanbeing experiences greater relief from phonophobia than the human beingwould have experienced two hours after receiving the same amount ofrizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and twenty-fourhours after the meloxicam and the rizatriptan are administered, thehuman being experiences greater relief from phonophobia than the humanbeing would have experienced twenty-four hours after receiving the sameamount of rizatriptan without the meloxicam.

In some embodiments, the human being has had prior triptan use beforereceiving the subject combination, such as a combination comprisingmeloxicam and rizatriptan.

In some embodiments, the human being receiving the subject combinationhas a score of 0 or 1 on the Migraine Treatment OptimizationQuestionnaire (mTOQ-4).

In some embodiments, the human being receiving the subject combinationhas, prior to receiving the subject combination, indicated that he orshe was “never” or “rarely” pain-free within two hours of treatment formost attacks.

In some embodiments, the human being receiving the subject combinationhas, prior to receiving the subject combination, indicated that one doseof medication “never” or “rarely” relieved the respondent's headache andkept it away for at least 24 hours.

In some embodiments, the human being receiving the subject combinationhas, prior to receiving the subject combination, indicated that he orshe is “never” or “rarely” comfortable enough with his or her migrainemedication to be able to plan his or her daily activities.

In some embodiments, the human being receiving the subject combinationhas, prior to receiving the subject combination, indicated that aftertaking his or her migraine medication, he or she “never” or “rarely”feels in control of his or her migraines enough so that he or she feelsthat there will be no disruption in his or her daily activities.

In some embodiments, the human being receiving the subject combinationhas, prior to receiving the subject combination, a history ofdepression.

In some embodiments, the human being receiving the subject combination,such as a combination comprising meloxicam and rizatriptan, hasmigraine, and may have a history of inadequate response to priormigraine treatments. In some embodiments, the human being havingmigraine does not have cluster headaches or other types of migraines. Insome embodiments, the human being having migraine does not have chronicdaily headache. In some embodiments, the human being having migrainedoes not have more than 15, 15-20, 20-25, 25-28, 28-30, or 30-31non-migraine headache days per month. In some embodiments, the humanbeing having migraine does not have a history of significantcardiovascular disease. In some embodiments, the human being havingmigraine does not have uncontrolled hypertension.

For some methods, administration of the dosage form may achieve areduction in pain that lasts at least about one hour, two hours, threehours, four hours, six hours, at least about eight hours, about eight toabout 24 hours, or about 24 hours. In other embodiments, administrationof the dosage form may achieve a reduction in pain that is observed atabout 10 minutes, at about 30 minutes, at about one hour, at about twohours, at about three hours, at about four hours, at about five hours,at about six hours, at less than 15 minutes, at less than 20 minutes, 30minutes, at less than one hour, at less than two hours, at less thanthree hours, at about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 60minutes, or other time period in a range bound by any of these values,after administration of the dosage form.

For some methods, administration of the dosage form or the subjectcombination may achieve a reduction in pain that lasts at least aboutone hour, at least about two hours, at least about three hours, at leastabout four hours, at least about six hours, at least about eight hours,about 8 to about 24 hours, or about 24 hours. In other embodiments,administration of the subject combination may achieve a reduction inpain that is observed at about 10 minutes, at about 30 minutes, at aboutone hour, at about two hours, at about three hours, at about four hours,at about five hours, at about six hours, at or within about 5 minutes,at or within about 10 minutes, at or within about 15 minutes, at orwithin about 20 minutes, at or within about 25 minutes, at or withinabout 30 minutes, at or within about 35 minutes, at or within about 40minutes, at or within about 45 minutes, at or within about 50 minutes,or at or within about 60 minutes, at two hours or less, at three hoursor less, or other time period bound by these ranges, afteradministration of the subject combination.

A human being that is treated for a disease or condition with the dosageforms described herein may be of any age. For example the person mayhave an age of about 10 years to about 90 years, about 20 years to about80 years, about 30 years to about 75 years, about 40 years to about 70years, about 1 year to about 16 years, about 80 years to about 95 years,about 16 years or more, about 18 years or more, about 20 years or more,about 25 years or more, about 30 years or more, about 40 years or more,about 45 years or more, about 50 years or more, about 55 years or more,about 60 years or more, about 65 years or more, or any other age in arange bounded by, or between, these values.

In some embodiments, a human being who is treated for migraine with thedosage forms described herein, for example comprising meloxicam,rizatriptan, SBEβCD, and a bicarbonate such as sodium bicarbonate, maybe of 18 years to 65 years of age, about 18-20 years of age, about 20-25years of age, about 25-30 years of age, about 30-40 years of age, about40-45 years of age, about 40-50 years of age, about 50-60 years of age,about 60-65 years of age, or any other age in a range bounded by, orbetween, these values.

In some embodiments, a human being who is treated for migraine with adosage forms described herein, such as a dosage form comprisingmeloxicam, rizatriptan, sulfobutyl ether-β-cyclodextrin (SBEβCD), and abicarbonate such as sodium bicarbonate, may be black or AfricanAmerican, white, or Asian. In some embodiments, the human being is blackor African American. In some embodiments, the human being is white. Insome embodiments, the human being is Asian.

In some embodiments, a human being that is treated for a disease orcondition with a dosage form comprising meloxicam or another NSAID hassuffered from the pain or condition associated with the pain for atleast 1 day, at least one week, at least 2 weeks, at least 1 month, atleast 6 weeks, at least 2 months, at least 3 months, at least 6 months,or at least 1 year, or any duration in a range bounded by, or between,these values.

In some embodiments, a human being that is treated for migraine with adosage form comprising meloxicam and rizatriptan has been diagnosed ofmigraine with or without aura as defined by the ICHD-3 criteria for atleast 3 months, at least 6 months, at least 1 year, at least 2 years,about 1-2 years, 2-3 years, or longer, or at least 1 year, or anyduration in a range bounded by, or between, these values.

In some embodiments, a human being has, or has had an average of, 2 to8, 2-3, 3-4, 4-5, 5-6, 6-7, or 7-8 moderate to severe migraines permonth, such as for at least the past month.

A cyclodextrin used in a dosage form with meloxicam could include acyclodextrin, a cyclodextrin derivative, and/or a salt thereof. Aninclusion complex of meloxicam and cyclodextrin may be morewater-soluble relative to the non-complexed meloxicam. The cyclodextrinmay be a naturally-occurring cyclodextrin (e.g., α, β, orγ-cyclodextrins) or a synthetic cyclodextrin. In some embodiments,α-cyclodextrins, derivatives, or salts thereof may be used.α-Cyclodextrins may include, but are not limited to,(2,3,6-tri-O-acetyl)-α-cyclodextrin,(2,3,6-tri-O-methyl)-α-cyclodextrin, (2,3,6-tri-O-octyl)-α-cyclodextrin,6-bromo-6-deoxy-α-cyclodextrin, 6-iodo-6-deoxy-α-cyclodextrin,(6-O-tertbutyl-dimethylsilyl)-α-cyclodextrin, butyl-α-cyclodextrin,succinyl-α-cyclodextrin, (2-hydroxypropyl)-α-cyclodextrin, orcombinations thereof.

In some embodiments, β-cyclodextrins, derivatives, or salts thereof maybe used. β-cyclodextrins may include, but are not limited to,hydroxypropyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin,glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin,6-O-α-D-glucosyl-β-cyclodextrin, 6-O-α-maltosyl-β-cyclodextrin,6-azido-6-deoxy-β-cyclodextrin,(2,3-di-O-acetyl-6-O-sulfo)-β-cyclodextrin, methyl-β-cyclodextrin,dimethyl-β-cyclodextrin (DMβCD), trimethyl-β-cyclodextrin (TMβCD),(2,3-di-O-methyl-6-O-sulfo)-β-cyclodextrin,(2,6-di-O-methyl)-β-cyclodextrin, (2,6-di-O-ethyl)-β-cyclodextrin,(2,3,6-tri-O-methyl)-β-cyclodextrin,(2,3,6-tri-O-acetyl)-β-cyclodextrin,(2,3,6-tri-O-benzoyl)-β-cyclodextrin,(2,3,6-tri-O-ethyl)-β-cyclodextrin, 6-iodo-6-deoxy-β-cyclodextrin,6-(dimethyl-tert-butylsilyl)-6-deoxy-β-cyclodextrin,6-bromo-6-deoxy-β-cyclodextrin, monoacetyl-β-cyclodextrin,diacetyl-β-cyclodextrin, triacetyl-β-cyclodextrin,(3-O-acetyl-2,6-di-O-methyl)-β-cyclodextrin,(6-O-maltosyl)-β-cyclodextrin, (6-O-sulfo)-β-cyclodextrin,(6-O-t-butyldimethylsilyl-2,3-di-O-acetyl)-β-cyclodextrin,succinyl-(2-hydroxypropyl)-β-cyclodextrin,(2,6-di-O-)ethyl-β-cyclodextrin, (2-carboxyethyl)-β-cyclodextrin(CMEβCD), hydroxyethyl-β-cyclodextrin (HEβCD),(2-hydroxypropyl)-β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin(HPβCD), (3-hydroxypropyl)-β-cyclodextrin (3HPβCD),(2,3-hydroxypropyl)-β-cyclodextrin (DHPβCD), butyl-β-cyclodextrin,methyl-β-cyclodextrin,silyl((6-O-tert-butyldimethyl)-2,3,-di-O-acetyl)-β-cyclodextrin,succinyl-β-cyclodextrin, (2-hydroxyisobutyl)-β-cyclodextrin, randomlymethylated-β-cyclodextrin, branched-β-cyclodextrin, or combinationsthereof.

In other embodiments, a β-cyclodextrin may be a sulfoalkyl ethercyclodextrin, derivative, or salt thereof. Examples of sulfoalkyl ethercyclodextrin derivatives may include, but are not limited to, sulfobutylether-β-cyclodextrin (e.g., SBEβCD, betadex, CAPTISOL®). In someembodiments, a SBEβCD may have about 4-8, about 5-8, about 4-7, about6-7, or about 6.5 sulfobutyl ether groups per cyclodextrin molecule.

In some embodiments, γ-cyclodextrins, derivatives, or salts thereof maybe used. γ-cyclodextrins may include carboxymethyl-γ-cyclodextrin,(2,3,6-tri-O-acetyl)-γ-cyclodextrin,(2,3,6-tri-O-methyl)-γ-cyclodextrin, (2,6-di-O-pentyl)-γ-cyclodextrin,6-(dimethyl-tert-butylsilyl)-6-deoxy-γ-cyclodextrin,6-bromo-6-deoxy-γ-cyclodextrin, 6-iodo-6-deoxy-γ-cyclodextrin,(6-O-t-butyldimethylsilyl)-γ-cyclodextrin, succinyl-γ-cyclodextrin,hydroxypropyl-γ-cyclodextrin (2-hydroxypropyl)-γ-cyclodextrin,acetyl-γ-cyclodextrin, butyl-γ-cyclodextrin, or combinations thereof.

In some embodiments, the dosage form may include a bicarbonate, such assodium bicarbonate, potassium bicarbonate, or a combination thereof. Abicarbonate may help to increase solubility and bioavailability of themeloxicam or rizatriptan.

Unless otherwise indicated, any reference to a compound herein, such asmeloxicam or a cyclodextrin, by structure, name, or any other means,includes pharmaceutically acceptable salts, alternate solid forms, suchas polymorphs, solvates, hydrates, enantiomers, tautomers,deuterium-modified forms, or any other chemical species that may rapidlyconvert to a compound described herein under conditions in which thecompounds are used as described herein.

In some embodiments, a dosage form may contain meloxicam in an amountfrom about 15-25 mg, about 18-22 mg, or about 20 mg. These doses may bea safe dose for repeated administration, such as once hourly dosing toonce daily dosing, twice daily dosing, dosing one to 12 times daily,doing 3, 4, 5, or 6 times daily, etc. In some embodiments, the meloxicammay be safely administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,or 15 times, or about 3 to about 10 times a day, once a day, or lessfrequently, such as once a week, once every two weeks, once a month,etc.

For any amounts of meloxicam described herein, salt forms of meloxicammay be present in the amounts recited above, or amounts that are molarequivalents to these amounts for the meloxicam free acid. For example,considering that the molecular weight of the meloxicam free acid is351.4 g/mol, 20 mg of meloxicam in the free acid form is 56.9 mmol.Thus, a molar equivalent amount of 20 mg of the meloxicam free acidwould be the mass of 56.9 mmol of meloxicam in a salt form. For example,the weight for the sodium salt of meloxicam (mw=373.4 g/mol), with thesame molar equivalent amount of 20 mg of the meloxicam free acid (or56.9 mmol), would be 21.25 mg. These doses may be safe for repeatedadministration, such as 1, 2, 3, or 4 times a day, or repeated at aninterval of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 4 weeks, 4-6weeks, about 1-2 months, about 6 weeks, about 2-3 months, about 3-4months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8months, about 8-9 months, about 9-10 months, about 10-11 months, about11-12 months or longer, etc.

For some dosage forms, meloxicam forms a complex with thesubstituted-β-cyclodextrin or other another cyclodextrin which may beformulated into a solid dosage form. Such a dosage form may be suitablefor oral administration. A meloxicam-cyclodextrin inclusion complex mayalso be dissolved in water or another solvent to form a parenteralformulation. However, physical mixtures of meloxicam and thesubstituted-β-cyclodextrin or other cyclodextrins may also be used inoral or parenteral dosage forms.

Formation of an inclusion complex of meloxicam and a cyclodextrin mayhelp to improve the properties of a dosage form. For some inclusioncomplexes, the meloxicam and the cyclodextrin (e.g., SBEβCD) may have amolar ratio of about 0.5-2 (a molar ratio of 0.5 is 0.5 moles ofmeloxicam to 1 mole of cyclodextrin), about 0.5-0.7, about 0.6-0.8,about 0.7-0.9, about 0.8-1, about 0.9-1.1, about 1-1.2, about 1.1-1.3,about 1.2-1.4, about 1.3-1.5, about 1.4-1.6, about 1.5-1.7, about1.6-1.8, about 1.7-1.9, about 1.8-2, about 0.8-1.2, about 1, or anyratio in a range bounded by any of these values.

For some dosage forms, a cyclodextrin (e.g., SBEβCD) may be employed ina weight ratio to the meloxicam within the range from about 1-1000(e.g., 1 g of cyclodextrin per 1 g of meloxicam is a weight ratio of 1);about 1-20; about 1-10; about 1-15; about 2-4, about 3-5, about 4-6,about 5-7, about 6-8, about 7-9, about 8-10, or any weight ratio in arange bounded by, or between, any of these values. For some dosageforms, a cyclodextrin (e.g., SBEβCD) may be employed in a weight ratioto the meloxicam within the range from about 0.001-1 (e.g. 0.1 g ofcyclodextrin per 1 g of meloxicam is a weight ratio of 0.1); about0.01-1; about 0.05-1; about 0.1-1; about 0.2-1; about 0.3-1, about0.4-1, about 0.5-1, about 0.6-1, about 0.7-1, about 0.8-1, or any weightratio in a range bounded by, or between, any of these values. Each typeof cyclodextrin employed may have a different ratio.

For some dosage forms, the cyclodextrin may be present in an amount fromabout 1-200 mg; 25-175 mg; about 50-150 mg; about 25-100 mg; about75-150 mg; about 100-175 mg; about 20-80 mg; about 25-50 mg; about60-100 mg; about 80-100 mg; about 80-120 mg; about 100-120 mg; about100-140 mg; about 120-160 mg; about 140-180 mg; about 30-90 mg; about40-80 mg; about 50-70 mg, about 55-65 mg, about 60-62 mg, or any amountin a range bounded by, or between, any of these values.

For some methods, the inclusion complex of meloxicam and cyclodextrinsuch as a substituted-β-cyclodextrin is delivered orally (for example bytablet, capsule, elixir, or the like). Other potential routes ofadministration include intravenous, intramuscular, intranasal,lyophilized parenteral, subcutaneous, transdermal, transmucosal, orthrough other parenteral means. The meloxicam may also be deliveredalone or non-complexed with cyclodextrin.

Some dosage forms contain a bicarbonate (e.g., sodium bicarbonate) inamount from about 1-2000 mg; about 1-1000 mg; about 100-1000 mg; about200-800 mg; about 1-500 mg; about 1-200 mg; about 1-100 mg; about 50-750mg; about 500-1000 mg; about 100-500 mg; about 100-300 mg; about500-1000 mg; about 300-700 mg; about 400-600 mg; about 50-250 mg; about250-750 mg; about 100-200 mg; about 200-300 mg; about 300-400 mg; about400-500 mg; about 410-510 mg; about 420-520 mg; about 430-530 mg; about440-540 mg; about 450-550 mg; about 460-560 mg; about 470-570 mg; about480-580 mg; about 490-590 mg; about 500-600 mg; about 600-700 mg; about700-800 mg; about 800-900 mg; about 150-650 mg; about 350-850 mg; or anyamount in a range bounded by, or between, any of these values.

In certain embodiments, the pharmaceutical composition results inincreased bioavailability (e.g., reduced T_(max), increased C_(max),increased AUC, etc.) of the meloxicam from the dosage form as comparedto a dosage form containing meloxicam but not containing a cyclodextrin,an acid inhibitor, or a buffering agent (such as a bicarbonate). In someembodiments, the bioavailability of meloxicam will increase withmultiple dosing.

Some of the dosage forms may result in a desired range for an area underthe plasma concentration curve (AUC) of meloxicam, such as anAUC_(0-inf) of meloxicam of about 40,000-70,000 ng*hr/mL; about50,000-60,000 ng*hr/mL; about 52,000-56,000 ng*hr/mL; or about 54,000ng*hr/mL.

In some embodiments, the dosage form may result in a C_(max) ofmeloxicam of about 2,500-3,500 ng/mL, about 2,700-3,100 ng/mL, or about2,900 ng/mL.

A method described herein may reduce the T_(max) of meloxicam. In someembodiments, the method may include treating a patient to achieve theT_(max) of meloxicam in the patient at about 0.5-1 hr, about 0.8-0.9 hr,or about 0.875 hr after administration of the subject combination.

Some of the dosage forms may result in a desired range for an area underthe plasma concentration curve (AUC) of rizatriptan, such as anAUC_(0-inf) of rizatriptan of about 70-100 ng*hr/mL; about 80-90ng*hr/mL; or about 86.7 ng*hr/mL.

In some embodiments, the dosage form may result in a C_(max) ofrizatriptan of about 25-35 ng/mL, about 30-34 ng/mL, about 31-32 ng/mL,or about 31.7 ng/mL.

A method described herein may reduce the T_(max) of rizatriptan. Forexample, the method may achieve a T_(max) of rizatriptan in the patientat about 0.5-1 hr, about 0.7-0.8 hr, or about 0.75 after administration.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form for direct oraladministration), and two hours after the meloxicam and the rizatriptanare administered, the human being experiences greater relief fromallodynia, such as cutaneous allodynia than the human being would haveexperienced two hours after receiving the same amount of meloxicamwithout the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and twenty-fourhours after the meloxicam and the rizatriptan are administered, thehuman being experiences greater relief from allodynia, such as cutaneousallodynia than the human being would have experienced twenty-four hoursafter receiving the same amount of meloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and two hoursafter the meloxicam and the rizatriptan are administered, the humanbeing experiences greater relief from allodynia, such as cutaneousallodynia than the human being would have experienced two hours afterreceiving the same amount of rizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g., in a single dosage form, such as a single oraldosage form, including a single solid oral dosage form), and twenty-fourhours after the meloxicam and the rizatriptan are administered, thehuman being experiences greater relief from allodynia, such as cutaneousallodynia than the human being would have experienced twenty-four hoursafter receiving the same amount of rizatriptan without the meloxicam.

In some embodiments, the dosage form may be formulated for oraladministration, for example, with an inert diluent or with an ediblecarrier, or it may be enclosed in hard or soft shell gelatin capsules,compressed into tablets, or incorporated directly with the food of thediet. For oral therapeutic administration, the active compound may beincorporated with an excipient and used in the form of ingestibletablets, buccal tablets, coated tablets, troches, capsules, elixirs,dispersions, suspensions, solutions, syrups, wafers, patches, and thelike.

Tablets, troches, pills, capsules and the like may also contain one ormore of the following: a binder such as gum tragacanth, acacia, cornstarch or gelatin; an excipient, such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; a sweetening agentsuch as sucrose, lactose or saccharin; or a flavoring agent such aspeppermint, oil of wintergreen or cherry flavoring. When the unit dosageform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier. Various other materials may be present ascoating, for instance, tablets, pills, or capsules may be coated withshellac, sugar or both. A syrup or elixir may contain the activecompound, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring, such as cherry or orange flavor. Itmay be desirable for material in a dosage form or pharmaceuticalcomposition to be pharmaceutically pure and substantially non-toxic inthe amounts employed.

Some compositions or dosage forms may be a liquid, or may comprise asolid phase dispersed in a liquid.

The dosage form may further comprise a second therapeutically activeagent, such as an acid inhibitor or an analgesic.

In some embodiments; a dosage form comprising the subject combinationmay contain rizatriptan in an amount of about 5-15 mg, about 8-12 mg, orabout 10 mg.

For acute migraines, the amount of meloxicam and/or rizatriptan in asingle dose, or the AUC of the meloxicam and/or rizatriptan associatedwith a single dose, is of particular interest. For example, after asingle dose, the symptoms may be relieved for an extended period oftime, such that, in the short term, repeated doses may not be needed.For more continuous conditions, including more chronic, continuous, orfrequent migraine symptoms, daily, weekly, or monthly doses may be ofparticular interest.

For any amounts of rizatriptan described herein, salt forms ofrizatriptan may be present in the amounts recited above, or amounts thatare molar equivalents to these amounts for the rizatriptan free base.For example, considering that the molecular weight of rizatriptan freebase is 269.4 g/mol, 10 mg of the rizatriptan free base is 37.1 mmol ofrizatriptan. Thus, the weight for a rizatriptan salt, with the samemolar equivalent amount of 10 mg of the rizatriptan free base, would bethe mass of 37.1 mmol of the rizatriptan salt. For example, for thebenzoate salt of rizatriptan (mw=391.2 g/mol), the molar equivalentamount of 10 mg of the rizatriptan free base (or 37.1 mmol), would be14.5 mg of rizatriptan benzoate. These doses may be safe for repeatedadministration, such as 1, 2, 3, or 4 times a day, or repeated at aninterval of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 4 weeks, 4-6weeks, about 1-2 months, about 6 weeks, about 2-3 months, about 3-4months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8months, about 8-9 months, about 9-10 months, about 10-11 months, about11-12 months, etc.

Some oral dosage forms may have enteric coatings or film coatings. Insome embodiments, a dosage form may comprise a tablet or a capsulehaving an enteric coating. In some embodiments, a dosage form maycomprise a tablet or a capsule having a film coating.

A dosage form comprising a combination of rizatriptan, and meloxicamdescribed herein may provide rapid relief of migraine pain in less than15 minutes, about 15 minutes, less than 30 minutes, 15-30 minutes, lessthan 1 hour, 0.5-0.75 hour, or 0.75-1 hour post dose. The combination ofrizatriptan and meloxicam described herein may provide relief ofmigraine pain that is numerically greater than rizatriptan at less than15 minutes, about 5 minutes, about 5-10 minutes, about 10-15 minutes,about 15 minutes, about 15-30 minutes, about 30-45 minutes, about 45-60minutes, about 1-1.5 hours, about 1.5-2 hours, about 2-2.5 hours, about2.5-3 hours, about 3-3.5 hours, about 3.5-4 hours, about 4-5 hours,about 5-6 hours, about 6-8 hours, about 8-10 hours, about 10-12 hours,about 12-24 hours, about 24-48 hours, or longer, post dose. Thepercentage of migraine patients reporting pain relief with the treatmentof a combination of rizatriptan, and meloxicam described herein may be1-100%, 3-100%, 4-100%, 5-100%, 3-5%, 5-10%, 10-20%, 20-30%, 30-40%,40-50%, 50-60%, 60-70%, 70-80%, 80-90%, 90-95%, or 95-100%.

The migraine patients receiving a dosage form comprising a combinationof rizatriptan and meloxicam described herein (“subject combination”)may achieve pain freedom at less than 2 hours, about 2 hours, about 2-3hours, about 3-4 hours, about 4-6 hours, about 6-8 hours, about 8-10hours, about 10-12 hours, about 12-16 hours, about 16-20 hours, about20-24 hours, about 24-30 hours, about 30-36 hours, about 36-40 hours,about 40-44 hours, about 44-48 hours, or longer post dose.

Example 1

A Phase 3, randomized, double-blind, multicenter, placebo- andactive-controlled trial was conducted to assess the efficacy and safetyof the combination of meloxicam and rizatriptan (meloxicam/rizatriptan)in the acute treatment of moderate and severe migraine. Eligiblepatients must have an age of 18 to 65 years, an established diagnosis(at least 1 year) of migraine with or without aura as defined by ICHD-3criteria, an average of 2 to 8 moderate to severe migraines per month,had a history of inadequate response to prior acute migraine treatments,assessed by a score of 7 using the Migraine Treatment OptimizationQuestionnaire (mTOQ-4) (the average score was 3.6), corresponding topoor response to prior acute treatments. Exclusion criteria includedcluster headaches or other types of migraines, chronic daily headache 15non-migraine headache days per month), history of significantcardiovascular disease, and uncontrolled hypertension. In addition to ahistory of inadequate response, enrolled patients exhibited a high rateof characteristics that are strongly associated with poor treatmentoutcomes including cutaneous allodynia (75.4%), severe migraine painintensity (41.2%), obesity (43.7%), and morning migraine (36.6%).

A total of 1,594 patients were randomized in a 2:2:2:1 ratio to receive(1) meloxicam/rizatriptan (20 mg meloxicam/10 mg rizatriptan, withSBEβCD (about 133.6 mg) and sodium bicarbonate (500 mg), (2) rizatriptan(10 mg), (3) meloxicam (20 mg) with SBEβCD (MoSEIC Meloxicam), or (4)placebo, to treat a single migraine attack of moderate or severeintensity. The two co-primary endpoints of the trial were the proportionof patients who are free from headache pain two hours after dosing, andthe proportion of patients who no longer suffered from their mostbothersome migraine-associated symptom (nausea, photophobia, orphonophobia) two hours after dosing, for meloxicam/rizatriptan ascompared to placebo.

Superiority of meloxicam/rizatriptan to the rizatriptan and meloxicamarms (component contribution) was to be established based on sustainedfreedom from headache pain from two to 24 hours after dosing (keysecondary endpoint). The study was conducted pursuant to an FDA SpecialProtocol Assessment (SPA). Rizatriptan, an active comparator in thetrial, is considered to be the fastest acting oral triptan and one ofthe most effective medications currently available for the acutetreatment of migraine. (Ferrari M D, Roon K I, Lipton R B, Goadsby P J.Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migrainetreatment: a meta-analysis of 53 trials. Lancet. 2001 Nov. 17;358(9294):1668-75.)

Meloxicam/rizatriptan provided rapid relief of migraine pain with thepercentage of patients achieving pain relief with meloxicam/rizatriptanbeing numerically greater than with rizatriptan at every time pointmeasured starting at 15 minutes, and statistically significant by 60minutes (p=0.04) (FIG. 1 ). The proportions of patients experiencingpain relief 1.5 hours after dosing were 60.5% for meloxicam/rizatriptancompared to 52.5% for rizatriptan and 48.3% for placebo (p=0.019,p=0.04, respectively versus meloxicam/rizatriptan) (FIG. 1 ). FIG. 1Ashows the percentage of subjects reporting pain relief over placebo formeloxicam, rizatriptan, and meloxicam/rizatriptan at 1.0 hour and 1.5hours.

Meloxicam/rizatriptan met the two regulatory co-primary endpoints bydemonstrating, with high statistical significance, a greater percentageof patients as compared to placebo achieving pain freedom (19.9% versus6.7%, p<0.001, FIG. 2 ), and absence of most bothersome symptom (36.9%versus 24.4%, p=0.002), 2 hours after dosing.

Superiority of meloxicam/rizatriptan to rizatriptan (active comparator)and MoSEIC™ meloxicam (component contribution) was established asspecified in the SPA, by the demonstration of a greater percentage ofpatients receiving meloxicam/rizatriptan achieving sustained painfreedom from 2 hours to 24 hours after dosing, compared to rizatriptan,MoSEIC™ meloxicam, and placebo (16.1%, 11.2%, 6.8% and 5.3%,respectively; p=0.038, p=0.001, and p<0.001, respectively versusmeloxicam/rizatriptan, FIG. 3A), the pre-specified key secondaryendpoint to demonstrate component contribution. About 80% of thepatients treated with meloxicam/rizatriptan who achieved pain freedom at2 hours maintained pain freedom through 24 hours. These resultsdemonstrated the significant improvement in pain freedom and superiorityof meloxicam/rizatriptan to rizatriptan in treating migraine.

Meloxicam/rizatriptan provided substantially greater and more sustainedmigraine pain relief compared to placebo and rizatriptan, whichtranslated to a significant reduction in rescue medication use formeloxicam/rizatriptan compared to placebo and rizatriptan. Thepercentage of patients experiencing sustained pain relief from 2 hoursto 24 hours after dosing was 53.3% for meloxicam/rizatriptan, comparedto 33.5% for placebo and 43.9% for rizatriptan (p<0.001, p=0.006,respectively versus meloxicam/rizatriptan) (FIG. 3B).

Sustained pain relief from 2 hours to 48 hours was also experienced by astatistically significantly greater proportion of meloxicam/rizatriptanpatients (46.5%), compared to placebo (31.1%) and rizatriptan (36.5%)patients (p<0.001, p=0.003, respectively versus meloxicam/rizatriptan)(FIG. 4B). FIG. 4D shows the percentage of subjects achieving sustainedpain relief over placebo from 2 hours to 48 hours for meloxicam,rizatriptan, and meloxicam/rizatriptan. The sustained pain freedom from2 hours to 48 hours was also experienced by a statisticallysignificantly greater proportion of meloxicam/rizatriptan patients(15.4%), compared to placebo (5.3%), and rizatriptan (8.8%), and MoSEIC™meloxicam (8.1%) patients (p<0.001, p=0.003, p=<0.001, respectivelyversus meloxicam/rizatriptan) (FIG. 4A). FIG. 4C shows the percentage ofsubjects achieving sustained pain freedom over placebo from 2 hours to48 hours for meloxicam, rizatriptan, and meloxicam/rizatriptan. About77% of patients treated with meloxicam/rizatriptan who achieved painfreedom at 2 hours maintained the pain freedom through 48 hours.

Rescue medication was used by 23.0% patients receivedmeloxicam/rizatriptan, compared to 43.5% patients received placebo and34.7% patients received rizatriptan (p<0.001 for each group versusmeloxicam/rizatriptan) (FIG. 5 ). About 77% of patients receivingmeloxicam/rizatriptan did not require rescue medication. These resultsdemonstrated the superiority of meloxicam/rizatriptan to rizatriptan, anactive comparator, in treating migraine.

Meloxicam/rizatriptan was statistically significantly superior torizatriptan on several other secondary endpoints, including PatientGlobal Impression of Change (PGI-C) (p=0.022), and return to normalfunctioning at 24 hours (p=0.027).

Some of the β-values for meloxicam/rizatriptan versus rizatriptan forvarious endpoints are listed in Table 1 below, demonstrating thestatistically significant superiority of meloxicam/rizatriptan overrizatriptan in treating migraine.

TABLE 1 P-Values for Meloxicam/Rizatriptan vs Rizatriptan for VariousEndpoints P-value Meloxicam/Rizatriptan Endpoint vs Rizatriptan 1 hourPain Relief 0.04 2-24 hour Sustained Pain Relief 0.006 2-48 hourSustained Pain Relief 0.003 2-24 hour Sustained Pain Freedom 0.038 2-48hour Sustained Pain Freedom 0.003 PGI-C 0.022 Functional Improvement at24 hours 0.027 Use of Rescue Medication <0.001

Given that Rizatriptan, an active comparator in the trial, is consideredto be the fastest acting oral triptan and one of the most effectivemedications currently available for the acute treatment of migraine, andthat this trial enrolled patients with difficult-to-treat migraine, theobserved treatment effects with meloxicam/rizatriptan that providedgreater and more lasting migraine pain relief than rizatriptan, ishighly significant. Many patients experience a suboptimal response totheir current acute migraine treatments, placing them at increased riskof headache related disability and progression to chronic migraine,factors associated with increased healthcare costs. The results of thisstudy suggest that meloxicam/rizatriptan may provide an importanttreatment option for people with difficult-to-treat migraine.Meloxicam/Rizatriptan was generally safe and well-tolerated during theMOMENTUM Phase 3 trials with adverse events occurring in one to threepercent of patients. 11.1% of patients experienced any form oftreatment-emergent adverse events after taking Meloxicam/Rizatriptan,while 2.7%, 1.6%, and 1.4% of patients experienced nausea, dizziness,and somnolence, respectively, after taking Meloxicam/Rizatriptan (Table2). The rate at which patients experienced treatment-emergent adverseevents after dosing with Meloxicam/Rizatriptan versus any of the othertested treatments was approximately similar (Table 2).

TABLE 2^(a) Meloxicam/ Rizatriptan Rizatriptan Meloxicam Placebo (N =441) (N = 434) (N = 433) (N = 218) Any 49 (11.1%) 67 (15.4%)  50 (11.5%)13 (6.0%) Treatment- Emergent Adverse Event Nausea 12 (2.7%)  21 (4.8%) 14 (3.2%) 8 (3.7%0 Dizziness 7 (1.6%) 9 (2.1%)  5 (1.2%) 5 (1.2%)Somnolence 6 (1.4%) 9 (2.1%) 10 (2.3%) 6 (1.4%) ^(a)Data presented asnumber of subjects (% of subjects)

The results of this trial demonstrate the ability ofmeloxicam/rizatriptan to provide unique benefits to migraine patients,with fast, strong, and durable relief of migraine pain as compared to apotent active comparator, rizatriptan, in a stringently designed trialenriched with patients with difficult-to-treat migraine. These resultshave potentially important implications for patient care based on thehigh rate of inadequate response to and patient dissatisfaction withcurrent treatments.

Meloxicam/rizatriptan incorporates multiple mechanisms of action toaddress various migraine processes with the goal of providing enhancedeffectiveness. Meloxicam/rizatriptan is thought to act by inhibitingCGRP release, reversing CGRP-mediated vasodilation, and inhibitingneuro-inflammation, pain signal transmission, and central sensitization.The results of this trial validate this approach, demonstrating thatmeloxicam/rizatriptan can provide significant benefit that is greaterthan that of currently available treatments, even in patients withdifficult-to-treat migraine. Meloxicam/rizatriptan may be used for theacute treatment of migraine in adults with or without aura effectively.

Example 2

More than 70% of sufferers report dissatisfaction with existing acutetreatments. The most commonly reported reasons for patientdissatisfaction are slow onset of pain relief, inconsistent pain relief,and recurrence of pain during the same day. Suboptimal acute treatmentis associated with an increased risk of chronic migraine which may beprevented by improving acute treatment outcomes.

The Migraine Treatment Optimization Questionnaire (mTOQ-4): evaluatestreatment efficacy of acute therapies based on 4 domains: pain freedom,sustained pain relief, comfort in planning daily activities, and lack ofdisruption in daily activities. Previous research indicates that between12-27% of people with migraine report rarely or never achieving apositive response on these items with treatment of other medications.

The clinical trial of Example 1 was analyzed to examine the proportionof subjects responding “Never” or “Rarely” to each of the mTOQ-4 itemsto characterize the areas of greatest unmet need in the acute treatmentof migraine.

The mTOQ-4 is a validated, reliable, self-reported, easy-to-use, 4-itemquestionnaire that assesses the adequacy of current treatment efficacyfor the purpose of optimizing treatment. The mTOQ-4 is shown in Table 3below.

TABLE 3 Less than Half the half the time mTOQ-4^(a) Never Rarely time ormore Q1 After taking your migraine 0 0 1 2 medication, are you pain-free within 2 hours for most attacks? Q2 Does one dose of your 0 0 1 2migraine medication usually relieve your headache and keep it away forat least 24 hours? Q3 Are you comfortable 0 0 1 2 enough with yourmigraine medication to be able to plan your daily activities? Q4 Aftertaking your migraine 0 0 1 2 medication, do you feel in control of yourmigraines enough so that you feel there will be no disruption to yourdaily activities? Subtotal for each column Total of all columns^(a)mTOQ-4 scores were determined based on prior treatments over thepreceding 4 weeks at screening.

The proportion of patients answering “never” or “rarely” to each of themTOQ-4 questions is depicted in FIG. 6 .

Example 3

A Phase 3, randomized, double-blind, multicenter, placebo-controlledtrial was conducted evaluating the early treatment of migraine withmeloxicam/rizatriptan. A total of 302 patients were randomized in a 1:1ratio to treat a single migraine attack with a single dose ofmeloxicam/rizatriptan (20 mg meloxicam/10 mg rizatriptan, with SBEβCD(about 133.6 mg) and sodium bicarbonate (500 mg) as described in Example1 above), or placebo, at the earliest sign of migraine pain, while thepain was mild, before progressing to moderate or severe intensity.

This clinical trial is different from the clinical trial in Example 1.The clinical trial of Example 1 enrolled only patients with a history ofinadequate response to prior acute treatments, with patients waiting totreat their attacks only when the migraine pain had reached moderate orsevere intensity. The clinical trial in Example 1 is in contrast to thisclinical trial, which enrolled all comers and in which patients wereinstructed to administer meloxicam/rizatriptan at the earliest sign ofmigraine pain while the pain was mild, before progressing to moderate orsevere intensity.

The patients were adult subjects with an established diagnosis ofmigraine with or without aura.

Co-primary endpoints are freedom from headache pain, and freedom fromthe most bothersome migraine-associated symptom (nausea, photophobia, orphonophobia), two hours after dosing, for meloxicam/rizatriptan ascompared to placebo.

Secondary endpoints included sustained pain freedom, freedom frommigraine pain progression, change in functional disability, and use ofrescue medication.

Inclusion criteria included male or female at ages 18-65 inclusive, anestablished diagnosis (at least 1 year) of migraine with or without auraas defined by the ICHD-3 criteria, and an average of 2 to 8 migrainesper month. Exclusion criteria included cluster headaches, tensionheadaches, or other types of migraines, chronic daily headache (15non-migraine headache days per month), history of significantcardiovascular disease, and uncontrolled hypertension.

Meloxicam/rizatriptan substantially and significantly eliminatedmigraine pain, and substantially and significantly prevented progressionof migraine pain intensity in this Phase 3 trial ofmeloxicam/rizatriptan in the early treatment of migraine. In the trial,meloxicam/rizatriptan met the co-primary endpoints of freedom frommigraine pain and freedom from most bothersome symptoms as compared toplacebo.

Meloxicam/rizatriptan demonstrated statistically significant improvementas compared to placebo on both of the co-primary endpoints of painfreedom (32.6% versus 16.3%, p=0.002), and freedom from most bothersomesymptom (43.9% versus 26.7%, p=0.003), 2 hours after dosing (FIG. 7A andFIG. 7B). The most bothersome symptom is nausea, photophobia, orphonophobia.

Meloxicam/rizatriptan was numerically superior to placebo as early as 30minutes for migraine pain freedom (FIG. 8 ) and most bothersome symptomfreedom (FIG. 9 ), achieving statistical significance for migraine painfreedom at 90 minutes (p=0.003) and at every time point thereafter (FIG.8 ). At 12 hours, 64% of the patients receiving meloxicam/rizatriptanwere pain free as compared to 42% of patients receiving placebo. At 24hours, 69% of patients receiving meloxicam/rizatriptan were pain free ascompared to 47% of patients receiving placebo.

Meloxicam/rizatriptan durably relieved migraine pain with astatistically significantly greater percentage of patients as comparedto placebo achieving sustained pain freedom from 2 to 24 hours afterdosing (22.7% versus 12.6%, p=0.030), and from 2 to 48 hours afterdosing (20.5% versus 9.6%, p=0.013) (FIG. 10A and FIG. 10B).

Meloxicam/rizatriptan prevented progression of migraine pain intensitybeyond mild in 73.5% of patients versus 47.4% of patients taking placebofrom 2 to 24 hours (p<0.001) (FIG. 11 ). A single dose ofmeloxicam/rizatriptan prevented migraine pain progression beyond mild.

The effect on pain progression translated to a significant reduction inthe use of rescue medication, with only 15.3% of patients takingmeloxicam/rizatriptan required rescue medication through 24 hours afterdosing, versus 42.2% of patients taking placebo (p<0.001) (FIG. 12 ).

Meloxicam/rizatriptan substantially and significantly reduced functionaldisability, and demonstrated overall disease improvement. The ability toperform normal activities was achieved by 73.5% of patients takingmeloxicam/rizatriptan compared to 47.4% of patients taking placebo at 24hours (p<0.001) (FIG. 13 ).

On the Patient Global Impression of Change (PGI-C) scale, 52.4% ofpatients taking meloxicam/rizatriptan were very much or much improvedcompared to 27.7% of patients taking placebo (p<0.001) at hour 2 (FIG.14 ).

Meloxicam/rizatriptan was generally safe and well tolerated in thetrial. The most commonly reported adverse events withmeloxicam/rizatriptan were somnolence, dizziness, and paresthesia, allof which occurred at a rate of less than five percent (Table 4). Therewere no serious adverse events in the trial.

TABLE 4^(a) Meloxicam/Rizatriptan Placebo (N = 140) (N = 143) AnyTreatment-Emergent 25 (17.9%) 11 (7.7%)  Adverse Event Somnolence 6(4.3%) 3 (2.1%) Dizziness 4 (2.9%) 2 (1.4%) Paresthesia 3 (2.1%) 0^(a)Data presented as number of subjects (% of subjects)

“[This] study demonstrated high rates of freedom from migraine pain withmeloxicam/rizatriptan treatment, and utilized an innovative design toevaluate migraine pain progression. It is remarkable that earlytreatment with meloxicam/rizatriptan prevented migraine pain progressionin the vast majority of patients and enabled a similarly high percentageof patients to return to normal functioning,” said Dr. Stewart Tepper,Professor of Neurology at the Geisel School of Medicine at Dartmouth.“The multiple mechanisms of meloxicam/rizatriptan address the manydisordered physiological processes implicated in migraine attacks. Theseresults, coupled with previous clinical data showing superiority ofmeloxicam/rizatriptan over an active comparator, provide clinicalevidence that this synergistic, multi-mechanistic approach and the rapidabsorption of meloxicam/rizatriptan may translate to important benefitsfor a wide range of patients. As clinicians continue to seek options fortheir patients with improved efficacy over currently availabletherapies, meloxicam/rizatriptan may offer an important new treatmentfor this disabling condition.”

This Phase 3 trial confirmed the superior and durable efficacy ofmeloxicam/rizatriptan. The prevention of migraine pain progression, andthe substantial increase in the rate of pain freedom demonstrated withearly treatment with meloxicam/rizatriptan, expands and enhances itsdifferentiated profile for the acute treatment of migraine. With thisPhase 3 trial and the Phase 3 trial described in Example 11 in patientswith a history of inadequate response to prior acute treatments,meloxicam/rizatriptan has now been evaluated in two positivewell-controlled trials. These trials demonstrated the efficacy ofmeloxicam/rizatriptan against potent active and placebo comparators,across a spectrum of migraine attack settings, regardless of the timingof migraine treatment, disease severity, or baseline pain intensity.

“Migraine is one of the most disabling disorders, incapacitatingsufferers and seriously damaging home life, social activity and theability to work. Published surveys have underscored that patients remaindissatisfied with the efficacy of currently available therapies,” saidCedric O'Gorman, MD, Senior Vice President of Clinical Development andMedical Affairs of Axsome. “The results of [this] trial demonstrate forthe first time that meloxicam/rizatriptan can halt migraine painprogression before reaching moderate or severe intensity. These datagrow the body of clinical evidence in support of the potential ofmeloxicam/rizatriptan to be a multi-mechanistic treatment for migrainewith efficacy that is superior to the current standard of care, andwhich can rapidly, robustly, and durably alleviate symptoms, and returnpatients to their normal daily activities.”

Example 4

The efficacy of meloxicam/rizatriptan compared to placebo was evaluatedin patient subgroups with the following risk factors for inadequatetreatment response to acute migraine medication: higher BMI, allodynia,morning migraine, and a history of depression.

The data was obtained from a pooled subgroup analyses from subjects whoparticipated in the clinical trials of Example 1 and Example 3 for theacute treatment of migraine.

As shown in FIG. 15 , across the four subgroups defined by risk factor,treatment with meloxicam/rizatriptan improved 24-hour sustained painfreedom rates compared to placebo.

For patients with a BMI that is greater than or equal to the median BMIof patients in the study median 28.8 kg/m²), 15.8% of treated patientshad pain freedom at two hours as compared to 7.6% of patients receivingplacebo (p=0.008).

For patients with presence of allodynia, as defined by a score onASC-12, 18.7% of treated patients had pain freedom at two hours ascompared to 8.1% of patients receiving placebo (p<0.001).

For patients with morning migraine, defined as a migraine attackoccurring before 10 am, 18.3% of treated patients had pain freedom attwo hours as compared to 8.1% of patients receiving placebo (p=0.005).

For patients with history of depression, 16.7% of treated patients hadpain freedom at two hours as compared to 5.9% of patients receivingplacebo (p=0.053).

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as amounts, percentage, and so forth usedin the specification and claims are to be understood in all instances asindicating both the exact values as shown and as being modified by theterm “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the specification and attached claimsare approximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the embodiments (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate theembodiments and does not pose a limitation on the scope of any claim. Nolanguage in the specification should be construed as indicating anynon-claimed element essential to the practice of the claims.

Groupings of alternative elements or embodiments disclosed herein arenot to be construed as limitations. Each group member may be referred toand claimed individually or in any combination with other members of thegroup or other elements found herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or to expedite prosecution. When any suchinclusion or deletion occurs, the specification is deemed to contain thegroup as modified thus fulfilling the written description of all Markushgroups if used in the appended claims.

Certain embodiments are described herein, including the best mode knownto the inventors for carrying out the claimed embodiments. Of course,variations on these described embodiments will become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventor expects skilled artisans to employ such variations asappropriate, and the inventors intend for the claimed embodiments to bepracticed otherwise than specifically described herein. Accordingly, theclaims include all modifications and equivalents of the subject matterrecited in the claims as permitted by applicable law. Moreover, anycombination of the above-described elements in all possible variationsthereof is contemplated unless otherwise indicated herein or otherwiseclearly contradicted by context.

In closing, it is to be understood that the embodiments disclosed hereinare illustrative of the principles of the claims. Other modificationsthat may be employed are within the scope of the claims. Thus, by way ofexample, but not of limitation, alternative embodiments may be utilizedin accordance with the teachings herein. Accordingly, the claims are notlimited to embodiments precisely as shown and described.

1. A method of treating migraine in patients with a history ofinadequate response to prior migraine treatments comprising, selecting apatient who, for at least the past four weeks: 1) has had 2 to 8migraines per month, and 2) according to the patient, is never or rarelycomfortable enough with the patient's migraine medication to be able toplan daily activities; and after the patient is selected, administeringa combination of 20 mg of meloxicam or a pharmaceutically acceptablesalt thereof and 10 mg of rizatriptan or a pharmaceutically acceptablesalt thereof to the patient during a migraine attack.
 2. The method ofclaim 1, wherein the meloxicam and the rizatriptan are present in asingle dosage form.
 3. The method of claim 2, wherein the dosage formfurther comprises a bicarbonate.
 4. The method of claim 2, wherein thedosage form further comprises a cyclodextrin.
 5. The method of claim 1,wherein the meloxicam and the rizatriptan are orally administered to thepatient.
 6. The method of claim 1, wherein the combination isadministered while the patient has mild migraine pain.
 7. The method ofclaim 1, wherein the combination is administered while the patient hasmoderate migraine pain.
 8. The method of claim 1, wherein thecombination is administered while the patient has severe migraine pain.9. The method of claim 3, wherein the dosage form further comprises acyclodextrin.
 10. The method of claim 4, wherein the cyclodextrin issulfobutyl ether-β-cyclodextrin (SBEβCD).
 11. The method of claim 9,wherein the cyclodextrin is sulfobutyl ether-β-cyclodextrin (SBEβCD).12. The method of claim 10, wherein the meloxicam is in an inclusioncomplex with SBEβCD.
 13. The method of claim 11, wherein the meloxicamis in an inclusion complex with SBEβCD.
 14. The method of claim 1,wherein the meloxicam is in the free acid form.
 15. The method of claim1, wherein the rizatriptan is in a salt form.
 16. The method of claim15, wherein the rizatriptan is present as rizatriptan benzoate.
 17. Themethod of claim 3, wherein the bicarbonate is sodium bicarbonate orpotassium bicarbonate.
 18. The method of claim 9, wherein thebicarbonate is sodium bicarbonate or potassium bicarbonate.
 19. Themethod of claim 17, wherein about 500 mg of sodium bicarbonate ispresent in the combination.
 20. The method of claim 18, wherein about500 mg of sodium bicarbonate is present in the combination.
 21. Themethod of claim 10, wherein about 133.6 mg of SBEβCD is present in thecombination.
 22. The method of claim 11, wherein about 133.6 mg ofSBEβCD is present in the combination.